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1.
Obstacles in elucidating the role of oxidative stress in?aging include difficulties in (1) tracking in?vivo oxidants, in (2) identifying affected proteins, and in (3) correlating changes in oxidant levels with life span. Here, we used quantitative redox proteomics to determine the onset and the cellular targets of oxidative stress during Caenorhabditis elegans' life span. In parallel, we used genetically encoded sensor proteins to determine peroxide levels in live animals in real time. We discovered that C.?elegans encounters significant levels of oxidants as early as during larval development. Oxidant levels drop rapidly as animals mature, and reducing conditions prevail throughout the reproductive age, after which age-accompanied protein oxidation sets in. Long-lived daf-2 mutants transition faster to reducing conditions, whereas short-lived daf-16 mutants retain higher oxidant levels throughout their mature life. These results suggest that animals with improved capacity to recover from early oxidative stress have significant advantages later in life. 相似文献
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Van Voorhies WA 《Aging cell》2002,1(2):91-101
Much of the recent interest in aging research is due to the discovery of genes in a variety of model organisms that appear to modulate aging. A large amount of research has focused on the use of such long-lived mutants to examine the fundamental causes of aging. While model organisms do offer many advantages for studying aging, it also critical to consider the limitations of these systems. In particular, ectothermic (poikilothermic) organisms can tolerate a much larger metabolic depression than humans. Thus, considering only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. In order to provide true insight into the aging process additional physiological processes, such as metabolic rate, must also be assayed. This is especially true in the nematode Caenorhabditis elegans, which can naturally enter into a metabolically reduced state in which it survives many times longer than its usual lifetime. Currently it is seen as controversial if long-lived C. elegans mutants retain normal metabolic function. Resolving this issue requires accurately measuring the metabolic rate of C. elegans under conditions that minimize environmental stress. Additionally, the relatively small size of C. elegans requires the use of sensitive methodologies when determining metabolic rates. Several studies indicating that long-lived C. elegans mutants have normal metabolic rates may be flawed due to the use of inappropriate measurement conditions and techniques. Comparisons of metabolic rate between long-lived and wild-type C. elegans under more optimized conditions indicate that the extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific to aging. 相似文献
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Female reproductive decline is one of the first aging phenotypes in humans, manifested in increasing rates of infertility, miscarriage, and birth defects in children of mothers over 35. Recently, Caenorhabditis elegans (C. elegans) has been developed as a model to study reproductive aging, and several studies have advanced our knowledge of reproductive aging regulation in this organism. In this review, we describe our current understanding of reproductive cessation in C. elegans, including the relationship between oocyte quality, ovulation rate, progeny number, and reproductive span. We then discuss possible mechanisms of oocyte quality control, and provide an overview of the signaling pathways currently identified to be involved in reproductive span regulation in C. elegans. Finally, we extend the relevance of C. elegans reproductive aging studies to the issue of human female reproductive decline, and we discuss ideas concerning the relationship between reproductive aging and somatic longevity. 相似文献
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We present a novel strategy that uses high-throughput methods of isolating and mapping C. elegans mutants susceptible to pathogen infection. We show that C. elegans mutants that exhibit an enhanced pathogen accumulation (epa) phenotype can be rapidly identified and isolated using a sorting system that allows automation of the analysis, sorting, and dispensing of C. elegans by measuring fluorescent bacteria inside the animals. Furthermore, we validate the use of Amplifluor as a new single nucleotide polymorphism (SNP) mapping technique in C. elegans. We show that a set of 9 SNPs allows the linkage of C. elegans mutants to a 5-8 megabase sub-chromosomal region. 相似文献
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A Genetic Pathway Conferring Life Extension and Resistance to Uv Stress in Caenorhabditis Elegans 总被引:8,自引:0,他引:8
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A variety of mechanisms have been proposed to explain the extension of adult life span (Age) seen in several mutants in Caenorhabditis elegans (age-1: an altered aging rate; daf-2 and daf-23: activation of a dauer-specific longevity program; spe-26: reduced fertility; clk-1: an altered biological clock). Using an assay for ultraviolet (UV) resistance in young adult hermaphrodites (survival after UV irradiation), we observed that all these Age mutants show increased resistance to UV. Moreover, mutations in daf-16 suppressed the UV resistance as well as the increased longevity of all the Age mutants. In contrast to the multiple mechanisms initially proposed, these results suggest that a single, daf-16-dependent pathway, specifies both extended life span and increased UV resistance. The mutations in daf-16 did not alter the reduced fertility of spe-26 and interestingly a daf-16 mutant is more fertile than wild type. We propose that life span and some aspects of stress resistance are jointly negatively regulated by a set of gerontogenes (genes whose alteration causes life extension) in C. elegans. 相似文献
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The cellular recycling process of autophagy is emerging as a central player in many of the conserved longevity pathways in C. elegans, but the underlying mechanisms that link autophagy and life span remain unclear. In a recent study, we provided evidence to suggest that autophagy modulates aging through an effect on lipid homeostasis. Specifically, we identified a role for autophagy in a longevity model in which germline removal in C. elegans extends life span. Life-span extension in these animals is achieved, at least in part, through increased expression of the lipase LIPL-4. We found that autophagy and LIPL-4-dependent lipolysis are both upregulated in germline-less animals and work interdependently to prolong life span. While these genetic results lend further support to a growing link between autophagy and lipid metabolism, our findings are the first to suggest a possible molecular mechanism by which autophagy modulates organismal aging. 相似文献
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Dramatic age-related changes in nuclear and genome copy number in the nematode Caenorhabditis elegans 总被引:1,自引:0,他引:1
The nematode Caenorhabditis elegans has become one of the most widely used model systems for the study of aging, yet very little is known about how C. elegans age. The development of the worm, from egg to young adult has been completely mapped at the cellular level, but such detailed studies have not been extended throughout the adult lifespan. Numerous single gene mutations, drug treatments and environmental manipulations have been found to extend worm lifespan. To interpret the mechanism of action of such aging interventions, studies to characterize normal worm aging, similar to those used to study worm development are necessary. We have used 4',6'-diamidino-2-phenylindole hydrochloride staining and quantitative polymerase chain reaction to investigate the integrity of nuclei and quantify the nuclear genome copy number of C. elegans with age. We report both systematic loss of nuclei or nuclear DNA, as well as dramatic age-related changes in nuclear genome copy number. These changes are delayed or attenuated in long-lived daf-2 mutants. We propose that these changes are important pathobiological characteristics of aging nematodes. 相似文献
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Autophagy is required for dietary restriction-mediated life span extension in C. elegans 总被引:2,自引:0,他引:2
Dietary restriction extends life span in diverse species including Caenorhabditis elegans. However, the downstream cellular targets regulated by dietary restriction are largely unknown. Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2(ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span. Since autophagy and longevity control are highly conserved from C. elegans to mammals, a similar role for autophagy in dietary restriction-mediated life span extension may also exist in mammals. 相似文献
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The nematode Caenorhabditis elegans has proven a robust genetic model for studies of aging, including the roles of oxidative stress and protein damage. In this review, we focus on the genetics of select long-lived (e.g., age-1, daf-2, daf-16) and short-lived (e.g., mev-1) mutants that have proven useful in revealing the relationships that exist among oxidative stress, life span, and protein oxidation. The former are known to control an insulin/IGF-1-like pathway in C. elegans, while the latter affect mitochondrial function. 相似文献
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Suda H Shouyama T Yasuda K Ishii N 《Biochemical and biophysical research communications》2005,330(3):839-843
It is well known that aging and longevity strongly correlate with energy metabolism. The nematode Caenorhabditis elegans is widely used as an ultimate model of experimental animals. Thus, we developed a novel tool, which is constructed from an optical detector, using an indirect method that can measure simply the energy metabolism of C. elegans. If we measure the oxygen consumption rate using this optical tool, we can easily evaluate the activity of mitochondria as an index in the aging process. However, a direct measurement of the oxygen consumption rate of C. elegans exposed in air is thought to be impossible because of the high concentration of atmospheric oxygen and the small size of the animals. We demonstrate here that we can directly detect the oxygen consumption with a small number of animals (相似文献
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Frequent germline mutations and somatic repeat instability in DNA mismatch-repair-deficient Caenorhabditis elegans 总被引:1,自引:0,他引:1
Mismatch-repair-deficient mutants were initially recognized as mutation-prone derivatives of bacteria, and later mismatch repair deficiency was found to predispose humans to colon cancers (HNPCC). We generated mismatch-repair-deficient Caenorhabditis elegans by deleting the msh-6 gene and analyzed the fidelity of transmission of genetic information to subsequent generations. msh-6-defective animals show an elevated level of spontaneous mutants in both the male and female germline; also repeated DNA tracts are unstable. To monitor DNA repeat instability in somatic tissue, we developed a sensitive system, making use of heat-shock promoter-driven lacZ transgenes, but with a repeat that puts this reporter gene out of frame. In genetic msh-6-deficient animals lacZ+ patches are observed as a result of somatic repeat instability. RNA interference by feeding wild-type animals dsRNA homologous to msh-2 or msh-6 also resulted in somatic DNA instability, as well as in germline mutagenesis, indicating that one can use C. elegans as a model system to discover genes involved in maintaining DNA stability by large-scale RNAi screens. 相似文献
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Van Voorhies WA 《Free radical biology & medicine》2002,33(5):587-596
Research into the causes of aging has greatly increased in recent years. Much of this interest is due to the discovery of genes in a variety of model organisms that appear to modulate aging. Studies of long-lived mutants can potentially provide valuable insights into the fundamental mechanisms of aging. While there are many advantages to the use of model organisms to study aging it is also important to consider the limitations of these systems, particularly because ectothermic (poikilothermic) organisms can survive a far greater metabolic depression than humans. As such, the consideration of only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. Additional physiological processes, such as metabolic rate, must also be assayed to provide true insight into the aging process. This is especially true in the nematode Caenorhabditis elegans, which has the natural ability to enter into a metabolically reduced state in which it can survive many times longer than its normal lifetime. The extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific for aging. 相似文献
16.
Luo Y 《Redox report : communications in free radical research》2004,9(2):65-69
Several investigators have generated long-lived nematode worms (Caenorhabditis elegans) in the past decade by mutation of genes in the organism in order to study the genetics of aging and longevity. Dozens of longevity assurance genes (LAG) that dramatically increase the longevity of this organism have been identified. All long-lived mutants of C. elegans are also resistant to environmental stress, such as high temperature, reactive oxygen species (ROS), and ultraviolet irradiation. Double mutations of some LAGs further extended life span up to 400%, providing more insight into cellular mechanisms that put limits on the life span of organisms. With the availability of the LAG mutants and the combined DNA microarray and RNAi technology, the understanding of actual biochemical processes that determine life span is within reach: the downstream signal transduction pathway may regulate life span by up-regulating pro-longevity genes such as those that encode antioxidant enzymes and/or stress-response proteins, and down-regulating specific life-shortening genes. Furthermore, longevity could be modified through chemical manipulation. Results from these studies further support the free radical theory of aging, suggest that the molecular mechanism of aging process may be shared in all organisms, and provide insight for therapeutic intervention in age-related diseases. 相似文献
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Stuart JA Brown MF 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2006,143(1):12-23
Animals are routinely faced with harsh environmental conditions in which insufficient energy is available to grow and reproduce. Many animals adapt to this challenge by entering a dormant, or quiescent state. In some animals, such as the nematode Caenorhabditis elegans, quiescence is coincident with increased stress resistance and longevity. Here we review evidence that the rules of life span extension established in C. elegans may be generally true of most animals. That is, that the rate of animal aging correlates inversely with cellular resistance to physiological stress, particularly oxidative stress, and that stress resistance is co-regulated with the quiescence adaptation (where the latter occurs). We discuss evidence for highly conserved intracellular signalling pathways involved in energy sensing that are sensitive to aspects of mitochondrial energy transduction and can be modulated in response to energetic flux. We provide a broad overview of the current knowledge of the relationships between energy, metabolism and life span. 相似文献
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Jessica T. Chang 《Autophagy》2018,14(7):1276-1277
Macroautophagy/autophagy is a cellular recycling process that is required for the extended life span observed in many longevity paradigms, including in the nematode C. elegans. However, little is known regarding the spatiotemporal changes in autophagic activity in such long-lived mutants as well as in wild-type animals during normal aging. In a recent study, we report that autophagic activity decreases with age in several major tissues of wild-type C. elegans, including the intestine, body-wall muscle, pharynx, and nerve-ring neurons. Moreover, long-lived daf-2/insulin-signaling mutants and glp-1/Notch receptor mutants display increased autophagic activity, yet with different time- and tissue-specific differences. Notably, the intestine appears to be a critical tissue in which autophagy contributes to longevity in glp-1, but not in daf-2 mutants. Our findings indicate that autophagic degradation is reduced with age, possibly with distinct kinetics in different tissues, and that long-lived mutants increase autophagy in a tissue-specific manner, resulting in increased life span. 相似文献